The present invention relates to novel phenazine carboxaldehydes and derivatives having antimicrobial and antineoplastic activity, to methods of preparing the novel compounds, to a purified strain of Streptomyces galanosa NRRL 15738 useful in the preparation of starting material for compounds of the present invention, and to a method for the use of compounds of the present invention as antimicrobial or antineoplastic agents.
The present invention also relates to novel compounds useful as intermediates in the preparation of the phenazine carboxaldehyde derivatives of the invention.
Phenazine compounds are known as natural products (see J. M. Ingram, et al, Adv. Appl. Microbiol., 13:267 (1970)), including phenazine-1-carboxamide (oxychloraphine), and methoxylated derivatives of phenazine-1-carboxylic acid (e.g., griseolutin).
Phenazine-1-carboxylic acid has been evaluated as an antitumor agent (see V. Chernetskii et al, Onkologyia (Kiev), 5:110 (1974) and O. A. Sidorik et al, Fiziol. Act. Veshch, 6:92 (1974)).
Substituted phenazine-1-carboxamides have also been evaluated for antitumor activity, and found active against sarcoma 180 (see K. Katagiri et al, Kenyu Nempo, 17:127 (1967)).
Phenazine-1-carboxamides bearing a tetrazole side chain have been evaluated as antiallergy agents (U.S. Pat. No. 4,337,579).
3,4-Benzophenazine-1-carboxamides bearing a variety of side chains including dimethylaminoethyl have been evaluated for antimicrobial activity (see H. Shoji et al, Yakugaku Zasshi, 103:245 1982)).
Phenazine-1,4-dicarboxamides bearing alkylamino and dialkylaminopropyl side chains have been evaluated for antimalarial activity (see S. N. Sawhney et al, J. Pharm. Sci., 68:524 (1979)).
The natural phenazine derivative, lomondomycin (also known in the literature as lomofungin), is reported as being produced in fermentation broths by the microorganism Streptomyces lomondensis NRRL 3252 (U.S. Pat. No. 3,359,165) and has been assigned the structure corresponding to 6-formyl-4,7,9-trihydroxy-1-phenazinecarboxylic acid, methyl ester (see C. G. Tipton, et al, J. Amer. Chem. Soc., 92(5):1425-1426 (1970)).